title: Intranasal and subcutaneous administration of dopamine D3 receptor agonists functionally restores nigrostriatal dopamine in MPTP-treated mice.
abstract: Parkinson's disease (PD) is a neurodegenerative disease with a hallmark motor defect caused by the death of dopaminergic neurons in the substantia nigra. Intranasal drug administration may be useful for Parkinson's treatment because this route avoids first-pass metabolism and increases bioavailability in the brain. In this study, we investigated the neuroprotection/neurorestoration effect of dopamine D3 receptor (D3R) agonists administered via both intranasal and subcutaneous routes in the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced PD mouse model. Furthermore, we employed D3R knock-out mice to validate the dependence on D3R signaling. We found that in wild-type mice, but not D3 receptor knockout mice, both intranasal and subcutaneous administration of D3R agonists rescue dopamine (DA) depletion in the striatum as well as DA neuronal death in the substantia nigra after MPTP treatment. Moreover, subcutaneous 7-OH-DPAT administration significantly improved gait performance (stride length and overall running speed) of MPTP-lesioned mice after 7 and 14 days of recovery. In addition, the distribution of D3 agonist 7-OH-DPAT was measured in designated brain areas by mass spectrometry analysis after subcutaneous and intranasal administration. Our data suggest that intranasal administration of D3R agonist would be a practical approach to treat PD.
authors.affiliation: Department of Physiology and Pharmacology, Graduate Institute of Biomedical Sciences, Healthy Ageing Research Center, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-Shan, Tao-Yuan, 333, Taiwan, ROC.
authors.forename: Chu Lan
authors.initials: CL
authors.lastname: Lao
authors.forename: Yen-Hsi
authors.initials: YH
authors.lastname: Kuo
authors.forename: Yueh-Ting
authors.initials: YT
authors.lastname: Hsieh
authors.forename: Jin-Chung
authors.initials: JC
authors.lastname: Chen
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000281:Administration, Intranasal; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000008:administration & dosage / Q000627:therapeutic use*; D059290:Dopaminergic Neurons / Q000378:metabolism; D005684:Gait / Q000187:drug effects; D007211:Indoles / Q000008:administration & dosage / Q000627:therapeutic use; D007279:Injections, Subcutaneous; D020267:MPTP Poisoning / Q000139:chemically induced / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050637:Receptors, Dopamine D3 / Q000819:agonists*; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage / Q000627:therapeutic use
chemical_list: D018491:Dopamine Agonists; D007211:Indoles; D050637:Receptors, Dopamine D3; D013764:Tetrahydronaphthalenes; C046649:ropinirole; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; C031349:7-hydroxy-2-N,N-dipropylaminotetralin; D004298:Dopamine